Báo cáo y học: "N-GAL: Diagnosing AKI as soon as possib"

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Available online http://ccforum.com/content/11/6/173 Commentary N-GAL: Diagnosing AKI as soon as possible Claudio Ronco Department of Nephrology, St Bortolo Hospital, Vicenza, Italy Corresponding author: Claudio Ronco, cronco@goldnet.it Published: 6 November 2007 Critical Care 2007, 11:173 (doi:10.1186/cc6162) This article is online at http://ccforum.com/content/11/6/173 © 2007 BioMed Central Ltd See related research by Zappitelli et al., http://ccforum.com/content/11/5/R84 Abstract applies to the late stages of AKI, when the organ function has been lost and replacement by artificial organ support is Early diagnosis of acute kidney injury (AKI) is often problematic, required. There are many contributions showing that due to the lack of suitable early biomarkers of renal damage and technology has evolved in parallel with the worsening of the kidney function. Neutrophil gelatinase-associated lipocalin (NGAL) as an early marker of AKI partially overcomes such limitations and clinical conditions of the patients being treated, and it is seems to demonstrate that diagnosing AKI in its early stages is because of this that the mortality in this condition has not possible and useful. Using genomic and protein microarray changed over the years [2,3]. This myth is finally undergoing technology, a series of molecules have been identified as potential scientific scrutiny and the reality is emerging. We are now markers for AKI; among them NGAL has been demonstrated to realizing that for a number of non-complicated AKI cases, rise significantly in patients with AKI but not in the corresponding mortality can be significantly reduced especially if an controls. Furthermore, this rise in NGAL occurs in various studies at 24 to 48 hours before the rise in creatinine is observed. NGAL adequate renal replacement therapy is provided [4]. Never- both in urine and plasma is an excellent early marker of AKI with an theless, high mortality rates still pertain to complicated cases area under the receiver operator characteristic curve (AUC) in the associated to multiple organ failure or septic syndromes [5]. range of 0.9. The study of Zappitelli et al. in critically ill children combines for the first time the new RIFLE classification (Risk, The story of early diagnosis is different. Only recently have we Injury, Failure, Loss, End-stage renal disease) of AKI with the validation of NGAL as an early marker of kidney injury. This discovered that most of the preventive measures for AKI innovative approach brings a new hope for a timely diagnosis of which are efficacious in the experimental settings do not AKI and thus a timely institution of measures for prevention and show comparable positive results in the clinical setting [6]. protection. This can be explained by the inability to identify the time of injury in the clinical setting. In the experimental models we The issue of the early diagnosis of acute kidney injury (AKI) apply the renal insult at a known time and thus we are able to has been debated for years. Partially this has been due to the apply the prevention or protection protocol timely and lack of a suitable and consistent definition. Other limitations effectively. In the real clinical presentation it is only seldom are the paucity of available experimental models of AKI and and in specific cases (for example, elective cardiac surgery) the inadequate capability of selected marker molecules to where we can capture the exact moment of kidney insult and detect the impairment of kidney function in real time. The put in place counter measures. In order to make a solid article by Zappitelli et al. on neutrophil gelatinase-associated diagnosis of AKI in its early phases we have been missing lipocalin (NGAL) as an early marker of acute kidney injury has adequate classification and staging criteria until only a few partially overcome the above mentioned limitations and years ago. In 2002, during the second Acute Dialysis Quality seems to demonstrate that diagnosing AKI in its early stages Initiative (ADQI) Consensus Conference held in Vicenza, a is possible and useful [1]. new classification of AKI called RIFLE (Risk, Injury, Failure, Loss, End-stage renal disease) was proposed based on the AKI prevention and therapy has as of yet been rather level of serum creatinine rise or urine output reduction [7]. The unsuccessful and unsatisfactory. The problem may lie in the RIFLE classification has been validated now in many papers inadequacy of the renal replacement therapies that we have and it is the most current and accurate tool to define the level applied so far; however, this is questionable and it only of AKI and the level of associated risk of mortality [8]. ADQI = Acute Dialysis Quality Initiative; AKI = acute kidney injury; AUC = area under the receiver operator characteristic curve; HF = heart failure; NGAL = Neutrophil gelatinase-associated lipocalin; RIFLE = Risk, Injury, Failure, Loss, End-stage renal disease. Page 1 of 2 (page number not for citation purposes)
Critical Care Vol 11 No 6 Ronco Now that we have RIFLE we may speculate that AKI can be typical clinical signs. Finally they must be adequate to diagnosed much earlier than in the past identifying a specific indicate treatment initiation (theranostics) enabling future category such as risk, injury or failure. Such definitions studies to compare efficiency and efficacy of therapeutic suggest that in some cases, the AKI process has begun measures and techniques. much earlier than can be detected by the rise in serum creatinine. Creatinine is a reliable marker of kidney function Thus, in the timeline of the AKI syndrome early biomarkers but its constant and slow production makes its rise small and represent a unique possibility for a timely diagnosis and late in the case of an acute injury. There remains a need for a intervention to protect the kidney from further insults and to much earlier marker in order to diagnose AKI as soon as prevent the tissue damage from the existing risk factors. If we possible. wait for the clinical clock to activate the alarm we will always be late. We need to diagnose AKI and treat it as soon as Using genomic and protein microarray technology, a series of possible. molecules have been identified as potential markers for AKI; Competing interests among them NGAL which is a 25 kDa protein, generally expressed in low concentrations, and is greatly increased in CR received a speaker fee from BIOSITE at the meeting of the case of epithelial damage [1,9,10]. In several papers ISM in Brazil on May 2007. NGAL has been demonstrated to rise significantly in patients References with AKI but not in the corresponding controls [11-13]. 1. Zappitelli M, Washburn KK, Arikan AA, Loftis L, Ma Q, Devarajan Furthermore, this rise in NGAL occurs in various studies at P, Parikh CR, Goldstein SL: Urine neutrophil gelatinase-asso- 24 to 48 hours before the rise in creatinine is observed. ciated lipocalin is an early marker of acute kidney injury in critically ill children: a prospective cohort study. Crit Care NGAL both in urine and plasma is an excellent early marker of 2007, 11: R84 AKI with an area under the receiver operator characteristic 2. Ronco C: Continuous dialysis is superior to intermittent dialy- curve (AUC) in the range of 0.9. The molecule still requires a sis in acute kidney injury of the critically ill patient. Nat Clin Pract Nephrol 2007, 3:118-9. complete evaluation in different clinical settings but the 3. Ronco C, Ricci Z, Bellomo R, Baldwin I, Kellum J: Management promise is both fascinating and scientifically sound. of fluid balance in CRRT: a technical approach. Int J Artif Organs 2005, 28:765-76. 4. Ronco C, Bellomo R, Homel P, Brendolan A, Dan M, Piccinni P, Today, there are many studies ongoing to elucidate the La Greca G: Effects of different doses in continuous veno- nature of the association between NGAL and AKI in the venous haemofiltration on outcomes of acute renal failure: a prospective randomised trial. Lancet 2000; 356:26-30. critical care settings. The same holds true in the setting of 5. Chertow GM, Burcick E, Honour M, Bonventre JV, Bates DW: different types of cardiac surgery, contrast induced nephro- Acute kidney injury, mortality, length of stay, and costs in hos- pathy, worsening renal function in heart failure (HF) and pitalized patients. J Am Soc Nephrol 2005, 16:3365-3370. 6. Ronco C, Bellomo R: Prevention of acute renal failure in the sepsis patients. critically ill. Nephron Clin Pract 2003, 1:C13-20. 7. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P: The ADQI workgroup: Acute renal failure - definition, outcome mea- The study of Zappitelli et al. in critically ill children combines sures, animal models, fluid therapy and information technol- for the first time the new RIFLE classification of AKI with the ogy needs: the Second International Consensus Conference validation of NGAL as an early marker of kidney injury. This of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004, 8:R204-212. innovative approach brings a new hope for a timely diagnosis 8. Uchino S, Bellomo R, Goldsmith D, Bates S, Ronco C: An of AKI and thus a timely institution of measures for prevention assessment of the RIFLE criteria for acute renal failure in and protection. Looking to the natural evolution of AKI, we hospitalized patients. Crit Care Med 2006, 34:1913-1917. 9. Schmidt-Ott KM, Mori K, Kalandadze A, Li JY, Paragas N, can identify different milestones along the timeline of the Nicholas T, Devarajan P, Barasch J: Neutrophil gelatinase-asso- syndrome. The injury begins inducing molecular modifications ciated lipocalin-mediated iron traffic in kidney epithelia. Curr Opin Nephrol Hypertens 2006, 15:442-449. that subsequently evolve into cellular damage. The cells start 10. Cowland JB, Borregaard N: Molecular characterization and to produce biomarkers of injury and only subsequently does pattern of tissue expression of the gene for neutrophil gelati- the clinical picture of the syndrome develop with the typical naseassociated lipocalin from humans. Genomics 1997, 45: 17-23, sign and symptoms. Therefore we could imagine that the 11. Mishra J, Dent C, Tarabishi R, Mitsnefes MM, Ma Q, Kelly C, Ruff molecular and cellular clocks always anticipate the clinical SM, Zahedi K, Shao M, Bean J, et al.: Neutrophil gelati- clock, which is always late. The biological clock of biomarkers naseassociated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 2005, 365:1231- displays an intermediate time in this progression but it most 1238. certainly is reflective of an earlier stage when compared to 12. Wagener G, Jan M, Kim M, Mori K, Barasch JM, Sladen RN, Lee HT: Association between increases in urinary neutrophil the clinical clock. gelatinase-associated lipocalin and acute renal dysfunction after adult cardiac surgery. Anesthesiology 2006, 105:485- We need biomarkers that are sensitive (early appearance) 491. 13. Devarajan P: Emerging biomarkers of acute kidney injury. and specific (typical of organ injury). They must be easy to Contrib Nephrol 2007, 156:203-212. detect and measure (possibly at bedside); they must correlate with severity (offering accurate prognosis), quanti- tatively describing the level of injury even in the absence of Page 2 of 2 (page number not for citation purposes)